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Opicapone (OPC) is an effective add-on medication for motor fluctuations in Parkinson's disease (PD), with a favorable safety and tolerability profile. Elderly PD patients are a great proportion of the real-world PD population, often underrepresented in clinical trials. This multicenter, retrospective, longitudinal study aimed to assess the real-world safety and tolerability of OPC in PD patients aged ≥ 65 years. Clinical-demographic data were collected at OPC initiation (T0) and at the last follow-up visit (T1). OPC-related adverse events (AEs) and reasons for discontinuation were recorded. Patients were compared according to age and treatment continuation. Logistic regression analyses were used to evaluate association between baseline features and occurrence of AEs and discontinuation. One-hundred and one elderly PD patients were included and followed up for 20.6 ± 18.8 months after OPC initiation. Overall, 49 patients (48.5%) reported AEs, and OPC was discontinued in 29 (28.7%) within 9.4 ± 15.3 months, with neuropsychiatric and cardiovascular/autonomic AEs being the most common reasons. Patients aged ≥ 75 years reported greater disease severity and frequency of AEs compared to younger patients, but similar discontinuation rates at follow-up. At T1, OPC discontinuers exhibited greater motor impairment and a lower total levodopa equivalent dose. Univariate analyses showed that age, disease stage, and comorbidity burden were significantly associated with AEs occurrence. In the multivariable analysis, disease stage remained the only significant baseline feature associated with AEs. OPC was generally well tolerated in this cohort of real-world elderly PD patients. Larger, prospective studies are warranted.